The long-term outcome of acute myocardial infarction depends on extent of myocyte loss and structural remodelling of remaining myocyte and non- myocyte compartments of the left ventricle. To assess the significance of connective tissue changes in the non-infarct region of the left ventricle, we studied explanted hearts of 10 men [age 41-62 (mean 55) years] with chronic ischemic cardiomyopathy and prior myocardial infarction. Healed infarct involved 21+/-8% (range 9-36%) of left ventricular mass as measured morphometrically from a mean of 10 transverse sections of the left ventricle (mean thickness 8 mm). Volume fraction of collagen in a circumferential transverse section of the left ventricle at mid-cavity was 24+/-7% (range 11-33%) and consisted of replacement (mean 16+/-8%) and interstitial fibrosis (mean 8+/-4%). Volume fraction of collagen in the non-infarct region of the left ventricle was significantly greater in patients with ischemic cardiomyopathy (mean 13%) compared to age-matched normal control hearts (mean 4%, p<0.01). Furthermore, total volume fraction of collagen in mid left ventricle correlated with indices of left ventricular systolic and diastolic function derived from exercise radionuclide angiography studies performed before cardiac transplantation [rest ejection fraction (7-21%; r=-0.86; p<0.05), exercise ejection fraction (6-23%; r=-0.86; p<0.01), time to peak filling rate (81-215 msec; r=0.89; p<0.05), and time to end-systole (266-480 msec; r=0.83; p<0.05)]. Thus, the non- myocyte compartment of the non-infarct region of the left ventricle undergoes significant remodelling which may contribute to the impairment of systolic and diastolic function in patients with ischemic cardiomyopathy.